It is known that prostaglandin I.sub.2 (PGI.sub.2) is a substance which is biosynthesized from arachidonic acid through prostaglandin H.sub.2 (PGH.sub.2) and has potent platelet aggregation inhibitory activity, vasodilative activity, lipid deposition inhibitory activity, and leukocyte activation inhibitory activity. As such, PGI.sub.2 is considered to be effective in the treatment of peripheral vascular diseases (e.g. peripheral embolism, vibration syndrome, Raynaud's disease, etc.), systemic lupus erythematosus, post-PTCA (percutaneous transluminal coronary angioplasty) arterial reobliteration/restenosis, atherosclerosis, thrombosis, diabetic neuropathy, hypertension, ischemic diseases (e.g. cerebral infarction, myocardial infarction, etc.), transient ischemic attack, and glomerulonephritis.
Meanwhile, WO 96/20925, for instance, reports a non-prostanoid PGI.sub.2 receptor agonist compound of the formula: ##STR2##
wherein R.sup.1 represents --X--(CH.sub.2).sub.n COOR.sup.3 wherein X represents --O--, --S-- or --CH.sub.2 --; R.sup.3 typically represents hydrogen or C.sub.1-5 lower alkyl; n represents 1-3; R.sup.2 typically represents --CR.sup.4.dbd.CR.sup.5 --O-- or --CR.sup.5.dbd.CR.sup.4 --O-- wherein R.sup.4 represents --(CH.sub.2).sub.m --Y--R.sup.8 wherein m represents 1-4; Y typically represents --O-- or --CH.sub.2 --; R.sup.8 typically represents phenyl; R.sup.5 typically represents hydrogen or C.sub.1-5 lower alkyl.
JP-A-62-252780 discloses an antiulcer tricyclic compound of the formula: ##STR3##
wherein X and Y independently represent hydrogen, halogen, lower alkyl or lower alkoxy; n represents 0-4; R.sub.1 represents hydrogen, lower alkyl, unsubstituted or substituted phenyl; R.sub.2 typically represents lower alkyl, unsubstituted or substituted phenyl, heterocyclic group or cyclic amino; R.sub.3 represents hydrogen, lower alkyl, or acyl; R.sub.2 and R.sub.3 optionally taken together represent cyclic amino.
PGI.sub.2 is by no means chemically and biologically stable enough for use as a medicine. Moreover, it is not clear-cut in the desired action or actions versus other actions, thus unavoidably inducing adverse drug reactions.
Meanwhile, no information is available on the relation of those known tricyclic compounds to the affinity for PGI.sub.2 receptors. Under the circumstances, there is a keen demand for creation of a compound structurally removed from PGI.sub.2 and yet having a high affinity for PGI.sub.2 receptors and acting as a PGI.sub.2 receptor agonist with improved chemical stability and stability against metabolism and greater clinical efficacy than PGI.sub.2, thus being very satisfactory for use as a medicine.
The inventors of the present invention explored for compounds having PGI.sub.2 receptor agonistic activity and succeeded in the creation of a compound of the formula: ##STR4##
wherein R.sup.1 represents hydrogen or a substituent group;
m represents an integer of 1 to 3; PA1 Ar represents an aromatic group which may be substituted; PA1 X represents a bond or a divalent straight-chain group which have 1 to 6 atoms and may be substituted; PA1 Y represents --S--, --O-- or --N(R.sup.2)-- wherein R represents hydrogen or a substituent group; PA1 Z represents --N.dbd. or --C(R.sup.3).dbd. wherein R.sup.3 represents hydrogen or a hydrocarbon group; PA1 ring A represents a benzene ring which may be substituted by a substituent in addition to a group of the formula: --O(CH.sub.2).sub.m COR.sup.1 wherein the respective symbols have the same meanings as defined above; and PA1 ring B represents a 5- to 7-membered ring which may be substituted, or a salt thereof, PA1 which compound is structurally characterized in that the benzene ring (ring A) of the tricyclic skeletal system of the formula: ##STR5## PA1 wherein the respective symbols have the meanings defined above, has a substituent group of the formula --O(CH.sub.2).sub.m COR.sup.1 wherein the respective symbols have the meanings defined above. PA1 (1) compound (I); PA1 (2) a compound of the above (1) wherein R.sup.1 is (i) hydrogen, (ii) a hydroxy which may be substituted by a C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl or C.sub.7-16 aralkyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.2-6 alkenyl which may be halogenated, C.sub.2-6 alkynyl which may be halogenated, C.sub.3-6 cycloalkyl which may be halogenated, C.sub.6-10 aryl, C.sub.7-11 aralkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.6-10 aryloxy, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.7-11 aralkyl-carbonyl, C.sub.1-6 alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, amidino, imino, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, 3- to 6-membered cyclic amino, C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl, di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio which may be halogenated, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl, C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10 arylsulfonyl, or (iii) an amino which may be substituted by 1 or 2 substituents selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6 alkynyl, C.sub.3-6 cycloalkyl, C.sub.6-14 aryl and C.sub.7-16 aralkyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C.sub.1-6 alkyl which may be halogenated, C.sub.2-6 alkenyl which may be halogenated, C.sub.2-6 alkynyl which may be halogenated, C.sub.3-6 cycloalkyl which may be halogenated, C.sub.6-10 aryl, C.sub.7-11 aralkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.6-10 aryloxy, C.sub.1-6 alkyl-carbonyl, C.sub.6-10 aryl-carbonyl, C.sub.7-11 aralkyl-carbonyl, C.sub.1-6 alkyl-carbonyloxy, C.sub.6-10 aryl-carbonyloxy, carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, amidino, imino, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, 3- to 6-membered cyclic amino, C.sub.1-3 alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C.sub.1-6 alkylsulfamoyl, di-C.sub.1-6 alkylsulfamoyl, C.sub.1-6 alkylthio which may be halogenated, C.sub.6-10 arylthio, C.sub.1-6 alkylsulfinyl, C.sub.6-10 arylsulfinyl, C.sub.1-6 alkylsulfonyl and C.sub.6-10 arylsulfonyl; PA1 (3) a compound of the above (1) wherein the group of the formula: --COR.sup.1 is carboxy which may be esterified or amidated; PA1 (4) a compound of the above (1) wherein R.sup.1 is hydroxy which may be substituted; PA1 (5) a compound of the above (1) wherein R.sup.1 is hydroxy; PA1 (6) a compound of the above (1) wherein m is 1; PA1 (7) a compound of the above (1) wherein Ar is a C.sub.6-14 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfo, C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy; PA1 (8) a compound of the above (1) wherein Ar is phenyl which may be halogenated; PA1 (9) a compound of the above (1) wherein X is a divalent group of the formula: --Xa.sup.1 --Xb.sup.1 -- wherein Xa.sup.1 is S, SO or SO.sub.2 ; and Xb.sup.1 is C.sub.1- 5 alkylene which may be substituted by a C.sub.6-14 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, C.sub.1-3 alkylenedioxy, nitro, cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy which may be halogenated, C.sub.1-6 alkylthio which may be halogenated, hydroxy, amino, mono-C.sub.1-6 alkylamino, di-C.sub.1-6 alkylamino, C.sub.1-6 alkyl-carbonyl, carboxy, C.sub.1-6 alkoxy-carbonyl, carbamoyl, mono-C.sub.1-6 alkyl-carbamoyl, di-C.sub.1-6 alkyl-carbamoyl, C.sub.6-10 aryl-carbamoyl, sulfol C.sub.1-6 alkylsulfonyl, C.sub.6-10 aryl and C.sub.6-10 aryloxy; PA1 (10) a compound of the above (9) wherein Xa.sup.1 is S; PA1 (11) a compound of the above (9) wherein Xb.sup.1 is a C.sub.1-3 alkylene which may be substituted by a phenyl which may be halogenated; PA1 (12) a compound of the above (1) wherein Y is --S--; PA1 (13) a compound of the above (1) wherein Z is --N.dbd.; PA1 (14) a compound of the above (1) wherein ring B is a ring of the formula: ##STR7## PA1 wherein Ba.sup.1 is --CH.sub.2 --, --(CH.sub.2).sub.2 --, --O--CH.sub.2 -- or --O--; PA1 (15) a compound of the above (1) which is a compound of the formula: ##STR8## PA1 wherein the respective symbols have the same meanings as defined above; PA1 (16) a compound of the above (15) wherein R.sup.1 is hydroxy; PA1 (17) a compound of the above (1) wherein R.sup.1 is hydroxy which may be substituted by a C.sub.1-6 alkyl; PA1 (18) a compound of the above (1) which is PA1 (19) a compound of the above (1) which is PA1 (20) a process for producing a compound of the above (1) which comprises PA1 (21) a compound of the formula: ##STR14## PA1 wherein X' represents SH, OH, or NH.sub.2 ; the other symbols have the same meanings as defined above or a tautomer thereof, or a salt thereof; PA1 (22) a pharmaceutical composition which comprises a compound of the above (1), if necessary together with a pharmaceutically acceptable carrier; PA1 (23) a composition of the above (22) which is for eliciting a prostaglandin I.sub.2 receptor agonistic effect; PA1 (24) a composition of the above (22) which is for inhibiting a platelet aggregation; PA1 (25) a composition of the above (22) which is for the prophylaxis or treatment of transient ischemic attack, diabetic neuropathy, peripheral vascular diseases or ulcer; PA1 (26) a method for eliciting a prostaglandin I.sub.2 receptor agonistic effect in a mammal in need thereof which comprises administering to such mammal an effective amount of a compound of the above (1) with a pharmaceutically acceptable excipient, carrier or diluent; and PA1 (27) use of a compound of the above (1) for manufacturing a pharmaceutical composition for eliciting a prostaglandin I.sub.2 receptor agonistic effect. PA1 a) C.sub.1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), PA1 b) C.sub.2-6 alkenyl (e.g. vinyl, allyl, isopropenyl, butenyl, etc.), PA1 c) C.sub.2-6 alkynyl (e.g. ethynyl, propargyl, butynyl, 1-hexynyl, etc.), PA1 d) C.sub.3-6 cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), PA1 e) C.sub.6-14 aryl (e.g. phenyl, 1-naphthyl, 2-naphthyl, 2-anthryl, etc.), PA1 f) C.sub.7-16 aralkyl (e.g. benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc.), preferably benzyl. PA1 (i) C.sub.1-5 alkylene (e.g. --CH.sub.2 --, --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, etc.) PA1 (iii) C.sub.2-5 alkynylene (e.g. --C.tbd.C--, --CH.sub.2 --C.tbd.C--, --CH.sub.2 --C.tbd.C--CH.sub.2 --, etc.) PA1 (iv) groups of the formula: --(CH.sub.2).sub.p --Xc--(CH.sub.2).sub.q -- wherein Xc represents S, SO, SO.sub.2, O, or NR.sup.4a ; p and q independently represent an integer of 0 to 4 and p+q is an integer of 0 to 4. R.sup.4a in this formula includes the same groups as those mentioned for R.sup.4. PA1 Ar is phenyl which may be halogenated; PA1 X is a divalent group of the formula: --Xa.sup.2 --Xb.sup.2 -- wherein Xa.sup.2 is S, SO or SO.sub.2 ; and Xb.sup.2 is C.sub.1-3 alkylene which may be substituted by a phenyl which may be halogenated; and PA1 ring B is a ring of the formula: ##STR17## PA1 wherein Ba.sup.2 is --CH.sub.2 --, --(CH.sub.2).sub.2 --, --O--CH.sub.2 -- or --O--. PA1 m is an integer of 1 to 3; PA1 Ar is C.sub.6-14 aryl which may be substituted by 1 to 3 substituents selected from the group consisting of halogen, nitro, cyano, C.sub.1-6 alkyl which may be halogenated, C.sub.1-6 alkoxy and C.sub.6-10 aryl; PA1 X is (i) a bond or (ii) a divalent group of the formula: --Xa.sup.3 --Xb.sup.3 -- wherein Xa.sup.3 is a bond, S, SO, SO.sub.2, O or NH; and PA1 Xb.sup.3 is a C.sub.1-5 alkylene or C.sub.2-5 alkenylene group which may be substituted by a phenyl which may be halogenated; PA1 Y is --S--; PA1 Z is --N.dbd.; PA1 ring A is a benzene ring which may be substituted by 1 to 3 C.sub.1-6 alkyl, in addition to a group of the formula: --O(CH.sub.2).sub.m COR.sup.1 ; and PA1 ring B is a ring of the formula: ##STR18## PA1 wherein Ba.sup.3 is --CH.sub.2 --, --(CH.sub.2).sub.2 --, --O--CH.sub.2 -- or --O--.
The inventors further discovered that because of the above unique chemical structure, the above compound or a salt thereof [hereinafter sometimes referred to briefly as compound (I)], is an excellent PGI.sub.2 receptor agonist having a high affinity for PGI.sub.2 receptors, high chemical stability, and high stability against metabolism and, thus, being fully satisfactory as a medicine. The present invention is predicated on the above findings.